The long range goal of this project is to contribute to our understanding of the role of the hormone glucagon in diabetes mellitus and in intracellular signaling in general. Our immediate goals are to design and synthesize peptide analogs that will be potent antagonists of the hormone, using as our principal tool, solid phase peptide synthesis. Our work will be guided by conformation predictions, X-ray data, NMR, and circular dichroism and their correlations with biological assay data. Such inhibitors are expected to aid in the studies of the mechanism of action of glucagon at the receptor level, and to provide a potentially therapeutic agent for in vivo regulation of blood glucose in the management of diabetes. We are extending the scope of our studies into the isolation of the glucagon receptor itself, and into post-receptor interactions that involve the regulatory guanine-nucleotide binding proteins. Purification and characterization of the receptor will be an invaluable tool in the study of hormone/receptor/G-protein/ effector interaction and will lead to an understanding of peptide hormone signal transduction and the control of diseases like diabetes mellitus.